Cooperative Driver Pathway Discovery by Hierarchical Clustering and Link Prediction

Identifying driver pathway is a critical step to uncover the natural laws of the occurrence and progression of disease. Many studies show that multiple pathways often function cooperatively in carcinogenesis. However, how to computationally identify cooperative driver pathways of cancers is not well studied yet. Existing cooperative driver pathway identification methods either suffer from single type of genetic information source or computation difficulty. In this paper, we proposed a method (CDPLP) based on hierarchical clustering and link prediction. CDPLP firstly devises a new similarity metric to quantity the exclusivity and co-expression of two gene modules, and thus to obtain gene sets with exclusivity by hierarchical clustering. Next, it uses link prediction on the pathway-pathway interaction network to replenish the interactions between pathways. After that, CDPLP combines the gene sets and updated pathway network to discover the pathway pairs with high functional interaction and occurrence as cooperative pathways. CDPLP can make full use of multiple genetic information sources such as the mutation data, gene-gene interaction data and pathway-pathway network, and facilitate the optimization solution. We evaluated the performance of CDPLP on TCGA breast cancer (BRCA) dataset and compared it with other popular methods. The results show that cooperative driver pathways identified by CDPLP are highly associated with the target cancer, and are involved with carcinogenesis and several key biological processes.